1. Field of the Invention
The present invention relates to a plasma separation apparatus and method adapted for effectively separating blood into plasma and corpuscular components including red and white corpuscles and elementary particles by using plasma separation membranes.
2. Description of Prior Art
Various blood treatment techniques such as hemodialysis using a dialysis membrane, hemofiltration with a filtration membrane and hemoperfusion with an adsorbent, among others, have come into wide clinical use. Recently, a technique called plasmapheresis, which is one of the extracorporeal blood treatment techniques, has been developed. Said plasmapheresis comprises first separating blood into plasma and corpuscular components and then treating the plasma by a certain technique, thereby removing pathogenic factors Among various plasmapheresis methods which have been proposed to date are:
(1) a method wherein blood is separated into plasma and corpuscular components through plasma separation membranes and then the plasma fraction containing pathogenic factors is discharged, the corpuscular fraction being returned to the circulation as it is or together with a plasma preparation in the same amount as the discharged plasma fraction;
(2) a method wherein blood is separated into plasma and corpuscular components through plasma separation membranes, then the plasma fraction containing pathogenic factors are brought into contact with an adsorbent so that the pathogenic factors are removed by adsorption, and subsequently said plasma fraction is mixed with the corpuscular fraction for return to the circulation (as disclosed in U.S. Pat. Nos. 4,013,564 and 4,243,532, for example);
(3) a method wherein from blood diluted with a plasma preparation is removed by separation through plasma separation membranes a plasma fraction equivalent to the quantity of the plasma preparation used for said dilution, the corpuscular components only of the blood being returned to the circulation;
(4) a method wherein blood is separated into plasma and corpuscular components through plasma separation membranes, then the plasma is further fractionated into a low-molecular-weight fraction and a high-molecular-weight fraction by means of plasma treatment membranes, so that the high-molecular-weight fraction, which contains pathogenic factors, is removed and the low-molecular-weight fraction is mixed with the corpuscular components for return to the circulation (as disclosed in U.S. Pat. No. 4,350,594, for example); and
(5) a method wherein blood is separated into plasma and corpuscular components through plasma separation membranes, then the plasma is cooled so that its high-molecular-weight component is allowed to gel, and the gel is removed through a filtration membrane, a low-molecular-weight fraction passed through the filtration membrane being mixed with the corpuscular component for return to the circulation (as disclosed in Artificial Organs Vol. 4, No. 3, pp. 205-207, June 1980, for example). To practice any of these methods, it is essential that blood should be efficiently separated into plasma and corpuscular components. Further teachings have already been made available on such separation methods and apparatuses therefor. For example, a Japanese patent application laid open under No. 110625/1981 discloses a method and apparatus wherein membranes having a pore diameter of 0.1-0.6.mu. are used to separate plasma from blood, with the trans-membrane pressure difference kept within a range of 50 mmHg-10 mmHg, so that the rate of plasma separation may be improved. Another Japanese patent application, laid open under No. 105707/1981 discloses a plasma separation apparatus such that if the trans-membrane pressure difference exceeds a predetermined value, the plasma pump is stopped and if the trans-membrane pressure difference regains the predetermined value, the pump is operated. However, these teachings are no more than proposals of possibilities or theoretical apparatus.
These techniques are such that the plasma discharge pump is ON-OFF controlled to prevent any abnormal increase in trans-membrane pressure differential, and therefore, once the plasma permeation performance of the membranes drops, it is necessary that the plasma pump should be subjected to frequent ON-OFF control. However, frequent ON-OFF manipulation of the plasma involves a difficulty in that at the instant the pump is actuated, the trans-membrane pressure differential may become excessively large, or the plasma discharge pressure may become negative, thus there being an increased chance of the corpuscular components of the blood being destroyed.
Prior to the development of the present invention, apparatus for plasma separation using plasma separation membranes suffered from several practical disadvantages which had limited their commercial exploitation. In particular, hitherto proposed apparatus incorporating plasma separation membranes were susceptible to at least three disadvantages; namely:
Hemolysis, that is the rupture or lysis of cells in the corpuscular component, was a significant problem. The semipermeable membranes used in plasma separators are intended to allow the plasma fraction of the blood to pass therethrough. As such, they have a larger pore size as compared to, for example, membranes used in blood dialysis apparatus. The result is that the cells of the corpuscular components of the blood being retained by the membranes, are very susceptible to hemolysis when the transmembrane pressure exceeds a certain level. To prevent hemolysis, it is therefore very important to ensure that the transmembrane pressure in the plasma separation apparatus does not exceed this certain level.
At the start of a plasma separation treatment for a patient, the passage of the plasma through the membrane of the separator causes the cells of the corpuscular blood components to be drawn to the surface of the membrane where they tend to accumulate. This in turn causes the pores of the membrane to become clogged with deposited cells so that the passage of plasma through the membrane becomes increasingly more difficult. The result is an increase in transmembrane pressure as the treatment of the patient progresses. This phenomenon is especially aggravated if the rate of plasma separation at the start of treatment is high, since the pores become quickly and irreversibly clogged. Not only does this mean that the rate of plasma withdrawn from the patient decreases quickly during treatment, but the increased transmembrane pressure due to clogging may cause an increased chance of hemolysis.
On commencing a plasma treatment process for a patient, the membrane is free of clogging cells so that the rate of separation of plasma from the blood is very high. This means that the amount of blood returned to the patient during the initial treatment phase is very low and can give rise to serious medical problems in the treatment of the patient.
U.S. Pat. No. 4,191,182 to Popovich et al. discloses a continuous plasmapheresis system employing ultrafiltration with a membrane to separate blood into plasma and cellular components. Popovich et al. also addresses the problem of preventing the membrane from clogging. For example, "(o)ne of these problems is that the flow rates must be controlled fairly closely. Thus, if the flow rate employed is too fast, turbulence will occur within the ultrafiltration cell which may cause hemolysis and the general destruction of cellular components. On the other hand, if flow rates and transmembrane pressures are not controlled adequately the cellular and macro-molecular components of the blood will tend to clog up the membrane thus significantly slowing the ultrafiltration rate. Such clogging can also cause hemolysis to occur." Further, "Continuous plasmapheresis is accomplished by continually withdrawing whole blood from a blood vessel and pumping same through an ultrafiltration chamber to effect separation of plasma and cellular components. The blood passes in laminar flow, parallel to the plane of the ultrafiltration membrane at flow rates sufficient to create shear stress across the ultrafilter membrane of from about 10 dynes/cm.sup.2 to about 1000 dynes/cm.sup.2."
An important distinction between the apparatus disclosed in Popovich et al. and the present invention is that the former is operated so that the pressure in the filtrate chamber is kept constant in order for the flow rate across the filtering side of the membrane to be kept constant, while the latter is operated so that the pressure in the filtrate chamber is varied in order that the pressure across the membrane is kept constant. As stated in the disclosure of Popovich et al., "the rate at which plasma pump 29 operates can be controlled such that the pressure in plasma outlet conduit 23 never varies from that necessary to maintain optimum transmembrane pressure regardless of the rate of ultrafiltration. Preferably the pressure in filtrate chamber 9b is kept at about atmospheric pressure at all times."
To illustrate the advantage of the present invention over the apparatus and method disclosed in the Popovich et al. patent, an experiment was conducted using a plasma separator built into the circuit shown in FIG. 4 herein. The same separator was also built into the circuit shown in FIG. 1 of the Popovich et al. patent.
The plasma separator was constructed by incorporating into a cylindrical cartridge a polyvinyl alcohol hollow fiber membrane having a substantially uniform microporous structure with an average pore size of 0.2 micron, an inside diameter of 330 microns, a membrane thickness of 125 microns and the membrane area being 0.5 m.sup.2.
With the plasma separator built into the circuit shown in FIG. 4 herein, the blood of a patient was treated. For plasma separation, the blood flow rate through blood pump was adjusted to 120 milliliters per minute (ml/mn). Concurrently, the plasma pump speed value was preset to 30 ml/min with the plasma pump speed setting circuit, and the value of the transmembrane pressure differential was set to 50 millimeters of mercury (mmHg) by the setting circuit. The transmembrane pressure differential was kept within 50 mmHg by gradually decreasing the rate of plasma discharge according to the degree of membrane clogging. With this method, the patient's blood was continuously treated for two hours. During that time, about 3.5 liters of fresh frozen plasma was pumped into the patient and about 3.5 liters of plasma was separated from the patient.
The same plasma separator was then built into the circuit shown in FIG. 1 of the Popovich et al. reference and the blood of the patient was treated. For plasma separation, the blood flow rate through the blood pump was adjusted to 120 ml/min, and the blood recycle pump speed value was set to 300 ml/min. The plasma pump speed was gradually decreased for maintaining the pressure in plasma outlet conduit at 0 mmHg. In addition, the plasma pump and the fresh frozen plasma pump were controlled in association with each other. The rate of flow of separated plasma was about 50 ml/min at the beginning but rapidly dropped with the lapse of time. In this manner, the blood was treated continuously for two hours. During this time, 2.8 liters of fresh frozen plasma was pumped into the patient and 2.8 liters of plasma was separated from the patient. It is noteworthy that the magnitude of a second pressure sensor at the outlet conduit randomly fluctuated during the treatment process within a range of about 50 mmHg to 135 mmHg when a resistance was provided at the outlet conduit due to the blood pressure of the patient connected to the apparatus.
This experiment illustrates the advantage, i.e., increased volume of plasma operation, of maintaining the transmembrane pressure constant in accordance with the present invention as compared with maintaining the flow rate constant in accordance with the disclosure of Popovich et al.